Scientists have investigated how small variations in DNA, called SNVs, can increase the risk of inherited cancer. They analyzed more than 4,000 such variations in human cells and identified 380 that may affect genes linked to cancer development. Among these genes, some are involved in DNA repair and cell growth that are involved in cancer processes.
Hereditary cancers are those caused by genetic mutations that can be passed down from generation to generation within a family. These mutations usually occur in genes that play a key role in regulating cell growth, DNA repair, and other processes that prevent cancer from developing.
Unlike sporadic cancers, which arise due to environmental factors and mutations accumulated over a lifetime, hereditary cancers tend to occur earlier in life and can affect multiple family members.
It is estimated that between 5% and 10% of all cancer cases have a hereditary predisposition, the most common being breast, ovarian, colorectal and prostate cancer, often associated with mutations in genes such as BRCA1, BRCA2 and MLH1.
Researchers at Stanford University School of Medicine, USA, have investigated how small variations in DNA, known as single nucleotide variants (SNVs), can influence the risk of developing hereditary cancer.
These variants are not located in genes that code for proteins, but rather in regulatory regions of DNA, which control the switching on or off of certain genes. To better understand their impact, more than 4,000 of these variants associated with 13 types of cancer that represent more than 90% of cancer cases in humans were analyzed.
The tests were performed on primary human cells relevant to each type of cancer and combined with data showing how these regions of DNA influence the accessibility of chromatin (the structure that organizes DNA within cells), the interaction between different parts of DNA and gene expression.
Using this approach, the researchers identified 380 variants that likely have a regulatory role and mapped the genes that may be affected by them.
Among the genes identified, those involved in processes essential to cancer stood out, such as the production of proteins in the mitochondria, the repair of DNA damage and the activity of a class of proteins called Rho GTPase, which influences the behavior of cancer cells.
In addition, using a technique called CRISPR to selectively disable some of these genes, scientists discovered that certain genes that increase the risk of cancer also help established tumors to grow.
One specific example analyzed was the rs10411210 variant, whose DNA editing revealed that the high-risk version of this variant increases the expression of the RHPN2 gene, involved in the activation of RhoA.
The rs10411210 variant was associated with the activation of the RhoA protein, which plays a crucial role in the dynamics of the cellular cytoskeleton, migration and cell invasion.
Alterations in this pathway are often linked to aggressive and metastatic cancers, especially those involving cell remodeling and tissue invasion. This suggests that certain variants may drive mechanisms that favor cancer progression.
A specific example of a cancer frequently associated with the activation of RhoA and genes such as RHPN2 is glioblastoma, an aggressive type of brain cancer. In addition, the RhoA pathway has also been implicated in cancers such as lung, breast and pancreatic carcinoma, in which dysregulated cell migration can lead to increased aggressiveness and metastasis.
These findings provide a valuable resource for prioritizing genetic variants in future research and deepening our understanding of the biological mechanisms that increase hereditary cancer risk. This may, in the future, contribute to more precise prevention and treatment strategies.
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Functional analysis of cancer-associated germline risk variants
Laura N. Kellman, Poornima H. Neela, Suhas Srinivasan, Zurab Siprashvili, Ronald L. Shanderson, Audrey W. Hong, Deepti Rao, Douglas F. Porter, David L. Reynolds, Robin M. Meyers, Margaret G. Guo, Xue Yang, Yang Zhao, Glenn G. Wozniak, Laura K. H. Donohue, Rajani Shenoy, Lisa A. Ko, Duy T. Nguyen, Smarajit Mondal, Omar S. Garcia, Lara E. Elcavage, Ibtihal Elfaki, Nathan S. Abell, Shiying Tao, Christopher M. Lopez, Stephen B. Montgomery & Paul A. Khavari
Nature Genetics (2025)
Abstract:
Single-nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays of 4,041 SNVs linked to 13 neoplasms comprising >90% of human malignancies were performed in pertinent primary human cell types and then integrated with matching chromatin accessibility, DNA looping and expression quantitative trait loci data to nominate 380 potentially regulatory SNVs and their putative target genes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, DNA damage repair and Rho GTPase activity. A CRISPR knockout screen demonstrated that a subset of germline putative risk genes also enables the growth of established cancers. Editing one SNV, rs10411210, showed that its risk allele increases rhophilin RHPN2 expression and stimulus-responsive RhoA activation, indicating that individual SNVs may upregulate cancer-linked pathways. These functional data are a resource for variant prioritization efforts and further interrogation of the mechanisms underlying inherited risk for cancer.
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